PROJECT SUMMARY Alzheimer?s disease (AD) is an age-dependent neurodegenerative disease characterized by progressive cognitive decline and neuropathology. It is well-documented that metabolic disorders increase the risk of AD and accelerate AD progression. However, the underlying molecular and cellular pathogenic mechanisms remain poorly understood. Adiponectin is a metabolic hormone that is produced almost exclusively by adipocytes. Its expression in adipose tissue is tightly regulated by peroxisome proliferator?activated receptor ? (PPAR?), a ligand-activated transcription factor. Adiponectin and PPAR?, two key players in maintaining metabolic homeostasis, have been implicated in the pathogenesis and treatment of AD. Adiponectin exerts neurotrophic effects and reverses cognitive deficits in a mouse model of AD. We found that adiponectin receptor subtypes AdipoR1 and AdipoR2 mediate distinct effects on neuronal excitability in AD-related brain regions. Aberrant neuronal hyperexcitability is a common feature in early state AD and contributes to selective vulnerability of neurons to degeneration. We hypothesize that an adipocyte-brain PPAR?/adiponectin/AdipoR axis plays an important role in the onset and progression of AD. The specific aims of this project are designed to 1) establish the role of the adipocyte PPAR?-adiponectin axis in age-dependent cognitive decline, metabolic dysregulation and neuropathology associated with AD; 2) identify the distinct functions of AdipoR1 and AdipoR2 at the systemic level and in glutamatergic neurons in the onset and progression of AD; and 3) determine the vulnerability of AdipoR1- and AdipoR2-expressing neurons to degeneration and the impact of selective activation or inhibition of these neurons on AD-related behavioral and neuropathological phenotypes.